Abstract
Metachromatic leukodystrophy (MLD) is a rare neurodegenerative disease that results from a deficiency of the lysosomal enzyme arylsulfatase A (ARSA). Worldwide, there are between one in 40,000 and one in 160,000 people living with the disease. While there are currently no effective treatments for MLD, induced pluripotent stem cell-derived brain organoids have the potential to provide a better understanding of MLD pathogenesis. However, developing brain organoid models is expensive, time consuming and may not accurately reflect disease progression. Using accurate and inexpensive computer simulations of human brain organoids could overcome the current limitations. Artificially induced whole-brain organoids (aiWBO) have the potential to greatly expand our ability to model MLD and guide future wet lab research. In this study, we have upgraded and validated our artificially induced whole-brain organoid platform (NEUBOrg) using our previously validated machine learning platform, DeepNEU (v6.2). Using this upgraded NEUBorg, we have generated aiWBO simulations of MLD and provided a novel approach to evaluate factors associated with MLD pathogenesis, disease progression and new potential therapeutic options.
Highlights
Michele Pavone and ValeriaMetachromatic leukodystrophy (MLD) is an autosomal recessive neurodegenerative metabolic disorder, of the lysosomal storage diseases (LSDs)
As described in the method section, the NEUBOrg/DeepNEU database (v6.2) contained a large number of phenotypic and genotypic features, which resulted in the generation of a large amount of data flowing through each node in the recurrent neural networks (RNN)
Summary of Artificially induced whole-brain organoids (aiWBO)–wild type (WT) Simulations Profile aiWBO–WT accurately predicted the expression of 43 elements consistent with wet lab whole-brain organoid profiles, and the presence of seven factors of compensated metabolic alkalosis and respiratory acidosis was consistent with wet lab findings
Summary
Metachromatic leukodystrophy (MLD) is an autosomal recessive neurodegenerative metabolic disorder, of the lysosomal storage diseases (LSDs). MLD is one of the most prevalent leukodystrophies (atrophy of the brain’s white matter) and has a prevalence rate of ~1 in 40,000–160,000 worldwide. Based on the type of mutation and degree of arylsulfatase A enzyme (ARSA) deficiency, MLD can show a wide spectrum of clinical manifestations that range from cognitive impairment to progressive abnormalities of motor and language function and early death [1,2]. As a secondary complication of MLD, unprocessed fats (i.e., sulfatides) accumulate within lysosomes and lead to lysosome dysfunction and the dysregulation of other lysosomal enzymes, leading to the complete disruption of lysosomal function and the eventual death of the affected cells (i.e., oligodendrocytes and neurons) [3]. Supportive measures can prolong life for some living with MLD
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